Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium that is a main cause of infections of the respiratory tract and can lead to severe invasive pneumococcal disease (IPD). More than 90 different pneumococcal serotypes have been described to date. These are classified by the structure of their capsular polysaccharide (CPS), which is unique to each serotype. Consequently, the immune response generated against the CPS varies between different serotypes. This is used to generate specific antibodies in rabbits against the antigen of each serotype. Cross-reactivity between these specific antibodies and other serotypes than those they were raised against is often observed, due to structural similarities of the CPS of different serotypes. Due to its immunological properties, CPS is used as the main component of S. pneumoniae vaccines.
The first efficient vaccine that contained the CPS of four different serotypes was described in 1945. It then took over thirty years until a vaccine was introduced that covered 14 serotypes, shortly followed by a 23-valent vaccine. However, these polysaccharide vaccines had several shortcomings. They were not able to elicit a long-lasting protection and were not effective in the populations most vulnerable to infection, namely children under two years of age as well as immunodeficient and elderly patients. These shortcomings result from the immunology of carbohydrates and were overcome by the introduction of carbohydrate-protein conjugate vaccines. The first pneumococcal conjugate vaccines were the seven-valent (PCV-7) and 10-valent (PCV-10) vaccine. PCV-7 was later replaced with the most recent vaccine (PCV-13), which contains the CPS-glycoconjugates of 13 different serotypes.
S. pneumoniae serotype 5 (SP5) is globally the fifth most prevalent IPD-causing serotype among young children, and the second most prevalent serotype amongst children in the poorest countries of the world, eligible to the support of the Global Alliance for Vaccines and Immunization (GAVI). Furthermore, SP5 was recently identified as the causative agent of an epidemic of severe pneumonia among young Israeli army recruits and community outbreaks of invasive infection in impoverished, urban populations in Canada. A very recent study showed that SP5 is a frequent cause of IPD outbreaks among children and adults in Spain. Although most SP5 subtypes are still susceptible to antibiotics, the emergence and dissemination of antibiotic-resistant SP5 bacteria is of concern.
The SP5 CPS is a component of the most recent PCV-10 and PCV-13 conjugate vaccines. The SP5 CPS consists of a branched pentasaccharide repeating unit with the sequence [→4)-β-D-Glcp-(1→4)-[α-L-PnepNAc-(1→2)-β-D-GlcpA-(1→3)]-α-L-FucpNAc-(1→3)-β-D-Sugp (1→], where Sugp is 4-keto-D-FucNAc (systematic name: 2-acetamido-2,5-dideoxy-D-xylo-hexos-4-ulose) and PneNAc is N-acetyl-L-pneumosamine (see FIG. 1).
The French patent application FR 2850106 A1 (AVENTIS PASTEUR, 23 Jul. 2004) describes conjugates obtained by reductive amination of SP5 CPS for use as vaccines against SP5. The saccharidic part of the conjugates are fragments of SP5 CPS isolated from bacterial sources containing in average 30 to 35 repeating units, wherein at least 85% of repeating units correspond to one of the following repeating units: [→4)-β-D-Glcp-(1→4)-[α-L-PnepNAc-(1→2)-β-D-GlcpA-(1→3)]-α-L-FucpNAc-(1→3)-β-D-Sugp (1→]; [→4)-β-D-Glcp-(1→4)-[α-L-PnepNAc-(1→2)-β-D-GlcpA-(1→3)]-α-L-FucpNAc-(1→3)-β-D-FucpNAc (1→]; and [→4)-β-D-Glcp-(1→4)-[α-L-PnepNAc-(1→2)-β-D-GlcpA-(1→3)]-α-L-FucpNAc-(1→3)-β-D-QuipNAc (1→]. The heterogenicity of the SP5 CPS fragments both in terms of size and structure is detrimental for the efficient manufacture of a well-defined vaccine.
It is the objective of the present invention to provide well-defined synthetic saccharides of general formula (I) that are related to the repeating unit of Streptococcus pneumoniae serotype 5 capsular polysaccharides. Said well-defined synthetic saccharides are suitable to be conjugated to an immunogenic carrier to provide conjugates and pharmaceutical compositions thereof that are useful for prevention and/or treatment of diseases associated with Streptococcus pneumoniae, and more specifically against diseases associated with Streptococcus pneumoniae serotype 5. Furthermore, the synthetic saccharides of general formula (I) are useful as marker in immunological assays for detection of antibodies against Streptococcus pneumoniae bacteria.
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.